Nuclear Expression of STAT6 Distinguishes Solitary Fibrous Tumor

Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics Leona A Doyle1, Marina Vivero1, Christopher DM Fletcher1, Fredrik Mertens2 and Jason L Hornick1

1Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA and 2Department of Clinical Genetics, University and Regional Laboratories, Ska˚ ne University Hospital, Lund University, Lund, Sweden

Solitary fibrous tumor (SFT) is composed of spindled to ovoid cells in a patternless architecture with prominent stromal collagen and hemangiopericytoma-like vessels. Some tumors show hypercellularity, nuclear atypia, and significant mitotic activity; the latter feature in particular often portends an aggressive clinical course. SFT can sometimes be difficult to distinguish from other benign mesenchymal tumors and sarcomas. The most characteristic (albeit nonspecific) immunohistochemical finding in SFT is CD34 expression. A NAB2–STAT6 gene fusion, resulting in a chimeric protein in which a repressor domain of NGFI-A binding protein 2 (EGR1 binding protein 2) (NAB2) is replaced with a carboxy-terminal transactivation domain from signal transducer and activator of transcription 6, interleukin-4 induced (STAT6), was recently identified as a consistent finding in SFT. However, as these genes are located in close proximity on 12q13, this fusion can only rarely be detected by conventional chromosomal banding or fluorescence in situ hybridization analysis. Nuclear expression of the carboxy terminal part of STAT6 is a consistent finding in SFT of the meninges (so-called ‘meningeal hemangiopericytoma’). We investigated STAT6 expression by immunohistochemistry in SFTs and other soft tissue tumors arising outside the central nervous system to validate the diagnostic utility of this novel marker. Whole-tissue sections of 231 tumors were evaluated, including 60 cases of SFT as well as other benign and malignant mesenchymal neoplasms and sarcomatoid mesotheliomas. Fifty-nine of 60 SFT cases (98%) showed nuclear expression of STAT6, which was usually diffuse and intense. All other tumor types were negative for STAT6, except for three dedifferentiated liposarcomas and one deep fibrous histiocytoma, which showed weak staining. In conclusion, STAT6 is a highly sensitive and almost perfectly specific immunohistochemical marker for SFT and can be helpful to distinguish this tumor type from histologic mimics. Modern Pathology (2014) 27, 390–395; doi:10.1038/modpathol.2013.164; published online 13 September 2013

Keywords: gene fusion; immunohistochemistry; sarcoma; soft tissue tumors; whole-exome sequencing

Solitary fibrous tumor (SFT) is an anatomically ubi- spindled to ovoid tumor cells with scant cytoplasm quitous fibroblastic neoplasm that most often affects and indistinct cell borders, in a ‘patternless’ archi- middle-aged adults. SFT was originally described in tecture. Prominent branching hemangiopericytoma- 1931 as a pleural tumor termed ‘hemangiopericytoma’,1 like vasculature is a characteristic finding, and the but over time it has been increasingly recognized that stroma is usually collagenous and hyalinized, occa- SFT may arise at a wide range of anatomical locations. sionally with myxoid areas.2–5 Lipomatous (fat- Of extrapleural tumors, B40% arise in subcutaneous forming) differentiation may also occur. The tumor tissue, with the remaining cases occurring in deep cells of SFT are usually bland, lacking significant soft tissues, retroperitoneum, mediastinum, abdominal atypia or pleomorphism, but atypical, cellular, and cavity, and meninges among other sites. malignant forms of SFT exist, reflecting the variable In its classic form, SFT shows variably hypo- (although sometimes unpredictable) biological cellular and hypercellular areas composed of potential of this tumor. SFT can sometimes be difficult to distinguish from some other benign mesenchymal tumors and spin- Correspondence: Dr JL Hornick, MD, PhD, Department of dle cell sarcomas, particularly in small biopsy Pathology, Brigham and Women’s Hospital, 75 Francis Street, samples. Immunohistochemistry using existing Boston, MA 02115, USA. E-mail: [email protected] markers is of variable utility in the differential Received 14 June 2013; revised 9 July 2013; accepted 14 July diagnosis. Traditionally, CD34 expression is the 2013; published online 13 September 2013 most consistent reported finding in SFT, present in

www.modernpathology.org STAT6 in SFT LA Doyle et al 391 up to 95% of cases. However, CD34 expression is diffuse hypercellularity or nuclear atypia, respec- also common in other tumors that may mimic SFT, tively, but without increased mitotic activity.16 In such as soft tissue perineurioma, dermatofibrosarcoma total, whole-tissue sections of 231 tumors were protuberans, and spindle cell lipoma. Furthermore, evaluated for expression of STAT6: 60 cases of SFT SFT shows nuclear expression of b-catenin in 40% (including 31 conventional (4 with prominent of cases, which may lead to confusion with desmoid myxoid stroma), 9 cellular, 5 atypical, and 15 malig- fibromatosis.6 SFT also shows reactivity for EMA in nant variants), 20 malignant peripheral nerve sheath 20–30% of cases7 and cytoplasmic staining for CD99 tumors, 10 sarcomatoid mesotheliomas, 10 cases of in B70% of cases.7,8 Positivity for BCL2 is seen in desmoid fibromatosis, 10 cellular schwannomas, 20 virtually all SFTs,7,9,10 but is a nonspecific finding, monophasic synovial sarcomas, 20 cases of dermato- as expression is also observed in a variety of other fibrosarcoma protuberans, 10 low-grade fibromyxoid mesenchymal neoplasms.9 sarcomas, 10 soft tissue perineuriomas, 10 deep Until recently, very little was known about the fibrous histiocytomas, 10 gastrointestinal stromal molecular genetics of SFT. However, using whole- tumors (spindle cell type), 21 dedifferentiated lipo- exome and transcriptome sequencing, three groups sarcomas, 10 spindle cell lipomas, and 10 cellular have recently identified NAB2–STAT6 gene fusions angiofibromas. Six of the cases of SFT were pre- in the vast majority of SFTs.11–13 These genes are viously shown to harbor the NAB2–STAT6 fusion located close together on chromosome 12 and are gene.13 transcribed in opposite directions. The fusion Immunohistochemistry for STAT6 was performed product results from an inversion at the 12q13 on 4-mm-thick formalin-fixed paraffin-embedded locus, which fuses NAB2 and STAT6. The resultant tissue sections following pressure cooker antigen fusion protein, in which a repressor domain of retrieval (0.01 M citrate buffer; pH, 6.0) using a NGFI-A binding protein 2 (EGR1 binding protein 2) rabbit polyclonal antibody directed against the C (NAB2) is replaced by a transactivation domain from terminus of STAT6 (1:1000; sc-621; Santa Cruz the carboxy terminal part of signal transducer and Biotechnology, Santa Cruz, CA, USA). Appropriate activator of transcription 6, interleukin-4 induced positive (SFT with genetically confirmed NAB2– (STAT6), is believed to act as a transcriptional STAT6 gene fusion) and negative controls were used activator through early growth response (EGR)- throughout. It is noteworthy that during antibody mediated pathways. In a study of mesenchymal optimization with low dilutions, weak nuclear stain- tumors of the central nervous system, Schweizer ing was observed in some normal cell types (vascular et al15 have identified the same fusion gene in endothelium, lymphocytes), whereas at higher dilu- meningeal SFTs and hemangiopericytomas, confirm- tions normal tissues were completely negative, but ing that meningeal ‘hemangiopericytoma’ is indeed a strong staining was seen in the nuclei of a SFT hypercellular variant of SFT (similar to the situation confirmed to have the NAB2–STAT6 fusion gene. The at other anatomical sites);14 the authors also extent of immunoreactivity was graded according to demonstrated that nuclear STAT6 protein over- the percentage of positive tumor cells (0, no staining; expression by immunohistochemistry is restricted 1 þ , o5%; 2 þ ,5–25%;3þ , 26–50%; 4 þ , 51–75%; to this tumor type among meningeal tumors. and 5 þ , 76–100%), and the intensity of staining was Although in most cases the diagnosis of SFT is graded as weak, moderate, or strong. relatively straightforward, some tumors may mimic other benign mesenchymal tumors or sarcomas, and a subset of SFTs lack expression of CD34. In this Results study, we investigated STAT6 protein expression by immunohistochemistry in SFT and histologic mi- The SFTs arose over a wide anatomic distribution, mics to validate the utility of STAT6 as a diagnostic including 10 in the extremities (6 lower and 4 marker. upper), 10 in the head and neck, 9 in the thoracic cavity (5 pleura, 3 lung, and 1 mediastinum), 7 in the abdominal cavity (including 1 each in the liver, Materials and methods uterus, pancreas, and urinary bladder), 7 in the pelvis, 6 in the retroperitoneum, 6 in the trunk, 4 in Cases were retrieved from the surgical pathology the inguinal region, and 1 in the meninges. The and consult files of Brigham and Women’s Hospital, results of immunohistochemistry for STAT6 are Boston, MA and Ska˚ne University Hospital, Lund, summarized in Table 1. Fifty-nine of 60 cases of Sweden, and the consult files of one of the authors SFT (98%) showed nuclear staining for STAT6, (CDMF). Representative hematoxylin and eosin- which was usually diffuse (5 þ in 41 cases; 4 þ in 6 stained slides were reviewed. Cases of SFT were cases; 3 þ in 5 cases; 2 þ in 3 cases; 1 þ in 4 cases) classified according to the WHO Classification of and intense (strong in 40 cases; moderate in 15 Tumors as conventional (classic), malignant (44 cases; and weak in 4 cases; Figure 1). In cases with mitoses per 10 high-power fields, with or without less than diffuse staining (ie, 1 þ or 2 þ ) and in four hypercellularity, atypia, and infiltrative growth), cases with strong expression, heterogeneous stain- and cellular or atypical in the presence of marked ing in a zonal distribution pattern was often seen,

Modern Pathology (2014) 27, 390–395 STAT6 in SFT 392 LA Doyle et al

with areas in the center of the tissue sections SFTs that were positive for STAT6, 4 were negative showing no (or weaker) staining, suggesting that for CD34, 54 were positive, and in 1 case CD34 this may be related to incomplete tissue fixation. expression status was unknown. The one SFT that was negative for STAT6 by All other tumor types were negative for STAT6 immunohistochemistry showed histological features (Figure 2), with the exception of 3 of 21 (14%) of malignancy, was positive for CD34, and was dedifferentiated liposarcomas, which showed pre- previously demonstrated to have a NAB2–STAT6 dominantly weak staining (4 þ weak in 1 case; 3 þ fusion gene. The remaining five SFTs known to weak in 1 case; 1 þ weak in the well-differentiated harbor the NAB2–STAT6 fusion gene showed diffuse component only of 1 case; Figure 3), and 1 of moderate-to-strong expression of STAT6. Of the 59 10 deep fibrous histiocytomas, which showed 1 þ weak nuclear staining. Eight tumors other than SFT (one low-grade fibromyxoid sarcoma, one spindle cell lipoma, one Table 1 Summary of immunohistochemical staining for STAT6 cellular angiofibroma, one cellular schwannoma, two cases of desmoid fibromatosis, and two malig- Total STAT6 positive nant peripheral nerve sheath tumors) showed a Tumor type cases (%) barely perceptible ‘blush’ of staining, but lacked Cellular angiofibroma 10 0 (0) a distinct nuclear pattern of expression and were Dedifferentiated liposarcoma 21 3 (14) therefore interpreted as negative. Desmoid fibromatosis 10 0 (0) Deep fibrous histiocytoma 10 1 (10) Dermatofibrosarcoma protuberans 20 0 (0) Gastrointestinal stromal tumor 10 0 (0) Discussion Low-grade fibromyxoid sarcoma 10 0 (0) Malignant peripheral nerve sheath tumor 20 0 (0) SFT is a fibroblastic neoplasm with variable clinical Monophasic synovial sarcoma 20 0 (0) behavior. Although most SFTs pursue a benign Sarcomatoid mesothelioma 10 0 (0) clinical course, recurrence or metastasis develops Schwannoma 10 0 (0) in 5–10% of patients. The majority of SFTs that Soft tissue perineurioma 10 0 (0) behave aggressively show histological features of Solitary fibrous tumor 60 59 (98) Spindle cell lipoma 10 0 (0) malignancy, such as 44 mitoses per 10 HPF and hypercellularity, but benign-appearing SFTs can

Figure 1 Classic solitary fibrous tumor (SFT) composed of bland spindle cells with dense stromal collagen and branching ‘hemangiopericytoma-like’ vessels (a). Most of the tumor cells show nuclear expression of STAT6, whereas vascular endothelial cells are negative (b). Cellular SFT; the tumor cells are ovoid and there is minimal stromal collagen (c). Diffuse, strong nuclear expression of STAT6 is observed in tumor cells (d). This example of malignant SFT, which showed conspicuous mitotic activity, resembled synovial sarcoma, with monomorphic spindle cells arranged in a somewhat fascicular architecture (e). The tumor cells show nuclear expression of STAT6 (f).

Modern Pathology (2014) 27, 390–395 STAT6 in SFT LA Doyle et al 393

Figure 2 Monophasic synovial sarcoma composed of fascicles of uniform spindle cells with overlapping nuclei (a). The tumor cells are negative for STAT6 (b). Cellular spindle cell lipoma may show some overlapping features with solitary fibrous tumor (SFT) (c). STAT6 is negative in tumor cells (d). also rarely give rise to metastases.17 Histologically, formation of a NAB2–STAT6 fusion gene, which can SFT may resemble some benign soft tissue tumors be detected by reverse transcriptase-PCR. However, (eg, soft tissue perineurioma, desmoid fibromatosis, as these genes are located in close proximity on spindle cell lipoma, and cellular angiofibroma); soft 12q13, this fusion can only rarely be detected by tissue tumors with potential for locally aggressive conventional chromosomal banding or fluorescence behavior (eg, desmoid fibromatosis); and spindle in situ hybridization (FISH) analysis. In the study by cell sarcomas (eg, malignant peripheral nerve Robinson et al,11 all 51 SFTs examined harbored the sheath tumor, dermatofibrosarcoma protuberans, NAB2–STAT6 fusion gene. A lower frequency of this and monophasic synovial sarcoma). The immuno- gene fusion was reported in the study by Chmielecki histochemical profile of SFT using conventional et al,12 being detected in just over 50% of cases, markers is relatively nonspecific, with CD34 expres- possibly reflecting diagnostic variability. Mohajeri sion being the most consistent finding reported to et al13 identified NAB2–STAT6 in 90% of SFTs date, present in 95% of cases. Other markers that evaluated. The fusion gene has not been identified are variably expressed in SFT include CD99, BCL2, in other soft tissue neoplasms studied to date. These nuclear b-catenin, and EMA. However, all these results have also been documented in meningeal markers are positive in other soft tissue tumors that SFTs (including tumors formerly known as menin- may mimic SFT. geal ‘hemangiopericytoma’).15 Several recent studies have detected a recurrent STAT6 is a member of the STAT family of cyto- intrachromosomal fusion between the NAB2 and plasmic transcription factors, which regulate gene STAT6 genes on chromosome 12 in SFT.11–13 This expression by transmitting signals to the nucleus genomic inversion at the 12q13 locus results in the and binding to specific DNA promoter sequences.

Modern Pathology (2014) 27, 390–395 STAT6 in SFT 394 LA Doyle et al

STAT611 and immunohistochemical analysis of STAT6 in SFT of the meninges, which showed diffuse nuclear expression in meningeal SFT, but not in other dural tumors.15 We found that 98% of a large cohort of SFTs (including conventional, cellular, atypical, and malignant variants) showed nuclear expression of STAT6. Staining for STAT6 was usually diffuse: 68% of cases showed reactivity for STAT6 in 475% of tumor cells. Further, the intensity of staining was strong in 67% of cases, moderate in 25%, and weak in only 7%. As discussed in the Results section, some tumors showed heterogeneity of staining, both in terms of extent and intensity, which may be because of uneven tissue fixation or loss of anti- genicity in older cases for which the unstained slides were stored for extended periods of time. All other tumor types examined were negative for STAT6, except for three dedifferentiated liposarcomas and one deep fibrous histiocytoma, which showed weak staining. Schweizer et al15 reported cytoplasmic expression of STAT6 in tumors other than SFT, albeit usually weak in intensity. In our study, cytoplasmic expression was not detected, which may reflect the higher dilution of antibody used in the current study. The finding of focal nuclear STAT6 expression in a subset of cases of dedifferentiated liposarcoma is interesting, and may suggest a role for STAT6- mediated transcriptional activity in some cases of dedifferentiated liposarcoma, given that the 12q13 locus contains several different regions that are frequently amplified in dedifferentiated liposarcoma, such as MDM2 and CDK4. In practice, dediffer- Figure 3 Dedifferentiated liposarcoma with highly atypical and entiated liposarcoma may enter the morphologic pleomorphic tumor cells within a fibromyxoid stroma (a). The differential diagnosis with SFT, particularly for tumor cells were positive for MDM2 and CDK4 (not shown) and showed focal weak nuclear expression of STAT6 (b). those tumors occurring in the retroperitoneum, and therefore the finding of STAT6 expression in dedifferentiated liposarcoma is a potential diagnostic pitfall. However, demonstration of positivity STAT signaling is critical for normal cellular for MDM2 and CDK4 by immunohistochemistry21,22 processes such as embryonic development, innate or MDM2 amplification by FISH23 can help confirm and adaptive immune function, and regulation of the diagnosis of dedifferentiated liposarcoma. cell differentiation, growth, and apoptosis.18,19 Acti- The discovery of a recurrent gene fusion by vation of STAT family members is a well-recognized whole-exome and transcriptome sequencing is a alteration in human malignancies.19 STAT6 is com- novel method of detecting translocation-associated posed of a DNA-binding domain, a C-terminal trans- sarcomas. In the case of SFT, such methods have criptional activation domain, and a SH2 domain. In resulted in the identification of a useful diagnostic contrast to STAT6, NAB2 normally functions as a immunohistochemical marker, STAT6, following transcriptional repressor through its interaction identification of the recurrent gene fusion product with the EGR family of transcription factors and NAB2–STAT6 in this tumor type. This adds to the is localized to the nucleus.20 However, NAB2 gains expanding group of markers for soft tissue tumors an activation domain when fused to STAT6, and identified through molecular genetic methods. For the NAB2–STAT6 fusion gene therefore acts as a example, gene expression analysis has previously transcriptional activator, inducing expression of identified ANO1 (anoctamin 1, calcium activated EGR target genes, which results in increased proli- chloride channel; also known as DOG1) as a specific feration.11 It is hypothesized that the fusion protein marker of gastrointestinal stromal tumor,24–27 TLE1 results in translocation to the nucleus and high (transducin-like enhancer of split 1) for synovial sar- levels of expression compared with normal tissues coma,27,28 and MUC4 (mucin 4, cell surface and other neoplasms, as demonstrated by immuno- associated) for low-grade fibromyxoid sarcoma.29,30 fluorescence labeling against the C terminus of Nuclear expression of STAT6 is found in nearly all

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